Sialoglycoproteomic network and target discovery for Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)是一种毁灭性的痴呆症，没有有效的治疗方法，强调了 需要更好地了解该病的致病机制并发现新的分子 作为治疗目标的脆弱性。该项目涉及AD的一个重要但研究不足的领域 研究并旨在发现唾液酸化介导的疾病过程和早期诊断的新靶点 和干预。蛋白质唾液酸化是一种翻译后修饰，可以共价连接唾液酸。 (带负电荷的九碳单糖，也称为神经氨酸)结合到糖蛋白上 产生唾液酸糖蛋白。越来越多的证据表明，唾液酸不仅在唾液酸糖蛋白上 影响蛋白质的构象、活性和运输，但也是分子和细胞的调节器 相互作用，充当阻止分子识别的生物面具和/或生物识别 介导与特定蛋白质相互作用的信号，如Siglecs(唾液酸结合免疫球蛋白- 类型凝集素)。蛋白质唾液酸化对大脑功能和体内平衡至关重要，这一事实突显了这一点 催化唾液酸化、去唾液酸化或唾液酸代谢酶的基因突变导致人类 有脑功能障碍和神经异常的疾病。此外，GWAS的研究已经确定 Siglec-3(也称为CD33)是AD的风险因素，强调了调控失调之间的联系 唾液酸化介导的信号转导与AD发病机制。然而，目前人们对人类知之甚少 脑唾液酸糖蛋白质组及其在AD中的变化拟议的项目将解决这一知识差距。 并使用一种创新的、多方面的方法，将唾液糖蛋白组学、网络生物学、细胞 在人类患者标本中发现和研究唾液糖蛋白质组的生物学和翻译研究 基于唾液酸化的分子机制和通路在健康和健康人群中潜在的脑功能 阿尔茨海默氏症。此外，该项目将进行大规模的高分辨率分析， 人阿尔茨海默病患者和对照脑脊液唾液糖蛋白质组的变化 确定用于早期诊断和监测疾病进展的新生物标记物。建议的调查结果 研究将促进我们对AD发病机制的理解，并为AD的诊断提供新的靶点 和治疗的发展。

Project Summary / Abstract Alzheimer's disease (AD) is a devastating dementia with no effective treatment, underscoring the critical need for better understanding the pathogenic mechanisms of this disease and uncovering new molecular vulnerabilities to target for therapy. This project addresses an important yet under-studied area of AD research and aims to discover sialylation-mediated disease processes and novel targets for early diagnosis and intervention. Protein sialylation is a post-translational modification that covalently attaches sialic acids (negatively charged nine-carbon monosaccharides also known as neuraminic acids) onto glycoproteins to generate sialoglycoproteins. Accumulating evidence indicates that sialic acids on sialoglycoproteins not only affect protein conformation, activity, and trafficking, but also serve as regulators of molecular and cellular interactions, acting as a biological mask for blocking molecular recognition and/or as a biological recognition signal for mediating interactions with specific proteins such as Siglecs (sialic-acid-binding immunoglobulin- type lectins). Protein sialylation is vital to brain function and homeostasis, as highlighted by the fact that genetic mutations in enzymes for catalyzing sialylation, desialylation, or sialic acid metabolism cause human diseases with brain dysfunction and neurological abnormalities. Furthermore, GWAS studies have identified Siglec-3 (also known as CD33) as a risk factor for AD, underlining the connection between dysregulated sialylation-mediated signaling and AD pathogenesis. However, very little is currently known about human brain sialoglycoproteome and its alterations in AD. The proposed project will address this knowledge gap and use an innovative, multi-faceted approach that combines sialoglycoproteomics, network biology, cell biology with translational research in human patient specimens to discover and study sialoglycoproteomic networks and sialylation-based molecular mechanisms and pathways underlying brain function in health and Alzheimer's disease. Furthermore, this project will perform large-scale high-resolution analyses of sialoglycoproteome changes in human AD and control cerebrospinal fluid, and blood serum samples to identify novel biomarkers for early diagnosis and monitoring disease progression. Findings from the proposed research will advance our understanding of AD pathogenesis and provide novel targets for AD diagnostic and therapeutic development.